Tobacco smoking is the number one health problem accounting for more illnesses and deaths in the US than any other factor. Despite efficacy of some current pharmacotherapies (i.e., nicotine replacement and bupropion), relapse rates continue to be high, indicating that novel medications are needed. Research in the current application proposes to develop a new class of subtype-selective nicotinic receptor (nAChR) antagonists as therapeutic agents with efficacy for tobacco use cessation and for treatment of nicotine dependence. As much as tobacco use behavior and nicotine addiction have links to depression, these novel drug candidates may also prove to be new treatments for depression. Based on the observations that the bupropion acts as a nAChR antagonist and that the nonselective nAChR antagonist, mecamylamine, has some efficacy as a tobacco use cessation agent, but is limited by its peripherally-mediated side-effect of constipation, we predict that the subtype-selective nAChR antagonists, which we propose to develop, may have therapeutic advantages and efficacy as tobacco use cessation agents in the treatment of nicotine addiction. We hypothesize that quaternizing the pyridine-N atom of the nicotine molecule with a lipophillic N-substituent to afford N-nicotinium analogs and/or by connecting these quaternary ammonium moieties with a lipophillic linker to afford N,N'-bis-analogs will result in subtype-selective nAChR antagonists, which will inhibit either nicotine-evoked dopamine, norepinephrine or serotonin release, and thus, inhibit nicotine-induced behaviors, indicating their potential as nicotine addiction treatments. Brain bioavailability, pharmacokinetics and metabolism of the lead candidates will also be evaluated. Comparison of results using native and recombinant nAChRs will provide new insights into the subunit composition of nAChRs mediating these functions. Drug candidates will be assessed for their ability to decrease nicotine self-administration, to decrease nicotine-induced reinstatement of nicotine seeking behavior, and to precipitate withdrawal in nicotine-dependent animals. Thus, an integrative approach (i.e., medicinal chemistry, pharmacokinetics, metabolism, pharmacology, psychology and neuroscience) will be used to increase our understanding of the underlying mechanisms of tobacco use and nicotine addiction, with focus on pharmacotherapeutic candidate development.